The Interchangeability and Substitutability Conundrum: Time for Convergence

The first blog post for this year was on interchangeability. In it I announced that SAHPRA has decided that biosimilars will be interchangeable with its reference products without requiring additional data to support such a claim. This decision followed that of the EMA, which published a statement on its website on September 19th, 2021, that it considered biosimilars interchangeable with their reference products from a scientific perspective.1 Previously, the EMA had left the decision on interchangeability to national regulatory agencies of EU member states. The reason for the change in the EMA position was to promote the use of biosimilars among physicians and their patients by confirming that biosimilars are indeed as safe and efficacious as the reference products.Almost a year has gone by and SAHPRA has yet to publish its new position on interchangeability. It should be noted, however, that the SAHPRA guideline on biosimilars has been archived; hence, it is likely that the new guideline will reflect SAHPRA’s changed position.

On October 26 of this year, the US FDA published updated labelling recommendations for biosimilars and interchangeable biosimilars.2 The FDA is perhaps the only regulatory agency that separates biosimilars into interchangeable and noninterchangeable categories, with the former requiring a switching or crossover clinical study in which participants that received the reference product initially are switched to the candidate biosimilar and vice versa. If the safety or efficacy profiles of the two treatments are equivalent then they are considered interchangeable, meaning that the biosimilar can be substituted for the reference product without compromising clinical outcomes or patient well-being. Hence, in the US, an interchangeable biosimilar is a biosimilar that can substitute a reference product without consulting the prescriber. Pharmacy-level substitution, as this is called, is subject to state law. This is unlike the situation in South Africa (and most EU member states), where the interchangeability decision rests with the treating physician; pharmacy-level substitution is currently not permitted. 

A recent study reported on the views of experts from European national medicines agencies and the pharmaceutical industry (innovator-only, biosimilar-only, and mixed innovator and biosimilar companies) on the interchangeability of biosimilars.3 Study participants indicated that interchangeability was more than a scientific question of likeness or similarity between a biosimilar and its reference product, i.e., that it also depended on regulatory practice and trust. Interestingly, most participants saw no need for additional scientific data to support substitution at the pharmacy level. They also did not believe that switching studies, as required by the US FDA, were appropriate as they were too small to deliver results that would be statistically significant. These findings imply that the decision not to allow pharmacy-level substitution is not because of a lack of scientific data to support such a policy, but because regulatory practice and (lack of) trust. Yet, regulatory agencies often claim that their decisions are based solely on science.  

It is widely recognised that access to biologics will only be promoted if greater competition exist in the market as this will drive down prices, making them affordable to all who need them. Thus, more biosimilars should be registered. Furthermore, regulatory barriers that limit their use, and which cannot be justified scientifically, i.e., based on quality, safety, efficacy, and comparability, should be removed. The time has arrived to allow for automatic substitution of reference biologics with biosimilars by pharmacists in terms of Act 101 of 1965.

References

  1. Biosimilar medicines can be interchanged. September 19, 2022. https://www.ema.europa.eu/en/news/biosimilar-medicines-can-be-interchanged
  2. Updated FDA libelling recommendations for biosimilars and interchangeable biosimilar products. October 26, 2023. https://www.fda.gov/drugs/our-perspective/updated-fda-labeling-recommendations-biosimilar-and-interchangeable-biosimilar-products

Druedahl LC, Kälvemark Sporrong S, Minssen T, Hoogland H, De Bruin ML, van de Weert M, et al. (2022) Interchangeability of biosimilars: A study of expert views and visions regarding the science and substitution. PLoS ONE 17(1): e0262537. https://doi.org/10.1371/journal.pone.0262537

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